The present invention relates to certain compounds of the formula (I) depicted below, which are useful in the synthesis of certain .beta.-adrenergic receptor agonists having the general formula Z ##STR4## where R.sup.1 and R.sup.2 are as defined herein for the compound of formula (I) and Y.sup.1, Y.sup.2 and Y.sup.3 are any chemical substituents which can be attached to the atoms to which Y.sup.1, Y.sup.2 and Y.sup.3 are attached and confer .beta.-adrenergic receptor activity and as such have utility as hypoglycemic and antiobesity agents, Y.sup.1 is preferably hydrogen. Examples of such substituents and the resultant .beta.-adrenergic receptor agonists can be found in PCT Publication No. WO 94/29290 published Dec. 22, 1994. The invention also relates to a process for synthesizing the compounds of formula (I) and to compounds of the formula (II), defined hereinbelow, which are useful in the synthesis of the compounds of formula (I). The invention also relates to a process for synthesizing a compound of formula (II). The invention further relates to processes for synthesizing compounds of formula (Z*), defined hereinbelow. The .beta.-adrenergic receptor agonists also possess utility for increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals.
The .beta.-adrenergic receptor agonists further possess utility in the treatment of intestinal motility disorders, depression, prostate disease, dyslipidemia, and airway inflammatory disorders such as asthma and obstructive lung disease.
The disease diabetes mellitus is characterized by metabolic defects in production and/or utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type II diabetes, or non-insulin dependent diabetes, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.
The .beta.-adrenergic receptor agonists effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
The .beta.-adrenergic receptor agonists also reduce body weight or decrease weight gain when administered to mammals and poultry. The ability of .beta.-adrenergic receptor agonists to affect weight gain is due to activation of .beta.-adrenergic receptors which stimulate the metabolism of adipose tissue.
.beta.-Adrenergic receptors have been categorized into .beta..sub.1 -, .beta..sub.2 - and .beta..sub.3 -subtypes. Agonists of .beta.-receptors promote the activation of adenyl cyclase. Activation of .beta..sub.1 -receptors invokes increases in heart rate while activation of .beta..sub.2 -receptors induces relaxation of skeletal muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of .beta..sub.3 -receptors is known to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids) and metabolic rate (energy expenditure), and thereby promote the loss of fat mass. Compounds that stimulate .beta.-receptors are, therefore, useful as anti-obesity agents, and can also be used to increase the content of lean meat in edible animals. In addition, compounds which are .beta..sub.3 -receptor agonists have hypoglycemic or anti-diabetic activity, but the mechanism of this effect is unknown.
Until recently .beta..sub.3 -adrenergic receptors were thought to be found predominantly in adipose tissue. .beta..sub.3 -receptors are now known to be located in such diverse tissues as the intestine (J. Clin. Invest., 91, 344 (1993)) and the brain (Eur. J. Pharm., 219, 193 (1992)). Stimulation of the .beta..sub.3 -receptor has been demonstrated to cause relaxation of smooth muscle in colon, trachea and bronchi. Life Sciences, 44(19), 1411 (1989); Br. J. Pharm., 112, 55 (1994); Br. J. Pharmacol., 110, 1311 (1993). For example, stimulation of .beta..sub.3 -receptors has been found to induce relaxation of histamine-contracted guinea pig ileum, J. Pharm. Exp. Ther., 260, 1, 192 (1992).
The .beta..sub.3 -receptor is also expressed in human prostate. Because stimulation of the .beta..sub.3 -receptor causes relaxation of smooth muscles that have been shown to express the .beta..sub.3 -receptor (e.g. intestine), one skilled in the art would predict relaxation of prostate smooth muscle. Therefore, .beta..sub.3 -agonists will be useful for the treatment or prevention of prostate disease.
Examples of .beta.-adrenergic receptor agonists which can be synthesized using the compounds of formula (I) can be found in PCT Publication No. WO 94/29290 published Dec. 22, 1994, U.S. patent application No. 08/312,027 filed Sep. 26, 1994, PCT Application No. PCT/IB95/00344 filed May 10, 1995 and United States Provisional Application No. 60/015,216 filed Apr. 9, 1996, all of which are assigned to the assignee hereof.
With regard to the process for synthesizing a compound of formula (II), defined hereinbelow, of the present invention, the chemical literature teaches that the addition of aryl halides (for example, bromobenzene, PhBr) to a vinyl ether of formula (IV) (see below) (for example, n-butyl vinyl ether when R.sub.4 is n-butyl) generally proceeds to afford a mixture of regioisomeric addition products resulting from addition of the aryl residue to either of the olefinic carbon atoms in the vinyl ether (Hallberg and Daves, Chemical Reviews, Vol. 89, 1989, page 1433). Thus, with bromobenzene and n-butyl vinyl ether, the addition products may be represented as PhCH.dbd.CHOBu and PhC(OBu).dbd.CH.sub.2. The product PhCH.dbd.CHOBu results from what is referred to as beta-arylation, in which the aryl group adds to the olefinic carbon atom distal to the oxygen atom of the vinyl ether. The product PhC(OBu).dbd.CH.sub.2 results from what is referred to as alpha-arylation, in which the aryl group adds to the olefinic carbon atom bonded to the oxygen atom of the vinyl ether. Furthermore, it has been well documented that when the aryl halide is substituted by electron withdrawing groups, such as the nitro group (for example, 4-bromo-1-nitrobenzene), the addition to the vinyl ether proceeds in such a way as to preferentially form the product of beta-arylation, O.sub.2 NC.sub.6 H.sub.4 CH.dbd.CHOBu, with the ratio of beta to alpha arylation generally exceeding 3 to 1 (Hallberg, Daves, and Andersson, Journal of Organic Chemistry, Vol. 52, 1987, 3529).
The chemistry of pyridines is frequently presented and thought of as being comparable to that of the corresponding nitrobenzenes, because of the significant electron deficiency of these ring systems, produced by the ring nitrogen atom in the case of pyridines and by the nitro substituent in the case of the nitrobenzenes (March, Advanced Organic Chemistry, 3rd Edition, 1985, page 461; Acheson, The Chemistry of Heterocyclic Compounds, 1960, page 167). Thus, pyridines and the corresponding nitrobenzene analogs undergo many of the same reactions that are usual in benzene chemistry, such as nucleophilic aromatic substitution, and fail many of the same reactions that are common in benzene chemistry, such as electrophilic aromatic substitution.
It will be apparent to one of ordinary skill in the art that, for the purposes of the present invention, the product of alpha arylation, which is represented by formula II, is required in order to furnish the desired compounds of formula (I) upon hydrolysis of the vinyl ether. Thus, one skilled in the art would not anticipate that pyridyl halides, such as those of formula (III), would afford synthetically useful quantities of the alpha-arylation products of formula (II).